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Aim: To determine the frequency of tumour budding and somatic APC mutation in a series of colorectal cancers stratified according to DNA microsatellite instability (MSI) status.
Material/Methods: Ninety five colorectal cancers were genotyped for APC mutation in the mutation cluster region (exon 15) and scored for the presence of tumour budding at the invasive margin in haematoxylin and eosin stained sections. A subset was immunostained for [beta] catenin and p16.
Results: The frequency of both somatic APC mutation and tumour budding increased pari passu in cancers stratified as sporadic MSI high (MSI-H), hereditary non-polyposis colorectal cancer (HNPCC), MSI low (MSI-L), and microsatellite stable (MSS). Both budding and APC mutation were significantly less frequent in sporadic MSI-H cancers than in MSI-L or MSS cancers. Tumour buds were characterised by increased immunostaining for both [beta] catenin and p16.
Conclusion: Tumour budding is associated with an adverse prognosis. The lack of budding in MSI-H colorectal cancer may account for the improved prognosis of this subset and may be explained by an intact WNT signalling pathway and/or inactivated [p16.sup.INK4a].
Prognosis in colorectal cancer has been associated with two morphological features seen at the invasive front of the primary tumour, namely: (1) the low magnification observation of diffuse infiltration and dissection of normal tissues by the cancer (1,2) and (2) the high magnification observation of tumour "budding". (3,4) These variables are correlated, with 80% of rectal cancers showing neither feature (64%) or both features (16%). (5) The five year survival rate associated with the presence of neither feature was 87%, both features 28%, and one or other feature around 50%. (5) Whereas the assessment of diffuse infiltration is subjective and shows considerable interobserver variation, tumour budding is a relatively reproducible feature. (5) In a multivariate analysis, tumour budding but not diffuse infiltration was identified as an independent prognostic factor. (5)
Tumour budding is defined as the presence of isolated single cells or small cell clusters (up to five) that are scattered in the stroma at the invasive margin of the tumour. (5) The buds appear to "drip" down from the main mass of more differentiated tumour. The loss of both glandular differentiation and cell cohesion that gives rise to these dissociated elements is probably a crucial event in the development of high invasive and metastatic properties. (6) This would be consistent with the important and independent adverse prognostic significance of tumour budding.
"The overexpression of [beta] catenin found in colorectal cancers is secondary to truncating mutation of the APC tumour suppressor gene"
[beta] Catenin has been implicated in the development of tumour budding. (7) Accumulation of nuclear [beta] catenin was demonstrated in dedifferentiated, mesenchyme-like tumour cells at the invasive front of colorectal cancers. In the remainder of the tumour, as in normal colorectal epithelium, [beta] catenin is expressed along the lateral cell membrane. (8) Analogies between patterning observed at the invasive tumour margin and in embryonic gastrulation have been drawn. (8) The overexpression of [beta] catenin found in colorectal cancers is secondary to truncating mutation of the APC tumour suppressor gene. As the principal effector of the WNT signalling pathway, nuclear [beta] catenin is able to complex with the T cell factor family of DNA binding proteins and function as a transcriptional activator. (9) Among the target genes activated by [beta] catenin are several known to be crucial in the process of invasion and metastasis. These include urokinase-like plasminogen activating receptor, (10) matrilysin, ( 11,12) CD44, (13) and laminin 5[gamma]2. (14)
Based on the model provided by the autosomal dominant condition, familial adenomatous polyposis, it has long been assumed that APC mutation is the initiating alteration in most colorectal cancers. (15) In fact, APC mutation is uncommon in small sporadic adenomas, (16,17) and the overall frequency of APC mutation in colorectal cancer is around 60%. (18) APC mutation is more frequent in rectal than colonic cancer. (19) Alternative mechanisms have been suggested for activating the WNT signalling pathway, including oncogenic …